There are currently 15.7 million people or 5.9% of the population in the United States who suffer from diabetes mellitus. Each day approximately 2,200 people are diagnosed with diabetes and roughly 798,000 people will be diagnosed this year. Diabetes is the seventh leading cause of death (sixth-leading cause of death by disease) in the United States.
Diabetes mellitus, more commonly known as diabetes, is a disease in which the body does not produce and/or properly use insulin, a hormone that aids the body in converting sugars and other foods into energy. In a non-diabetic individual, insulin is produced in the pancreas at the islets of Langerhans in response to an increase of glucose in the gut and/or blood. Insulin then acts in conjunction with the liver to control glucose metabolism in the body. While diabetes is typically thought of as a blood-sugar disease, diabetes may result in numerous life-threatening complications. For example, diabetes may lead to various microvascular diseases, such as retinopathy, nephropathy, and neuropathy. In the United States, diabetes is the leading cause of new cases of blindness in people ages 20 to 74, is the leading cause of end-stage renal disease, and is the most frequent cause of lower limb amputations. Diabetic individuals also have a higher likelihood of developing life-threatening macrovascular diseases, such as heart disease and stroke.
Several types of diabetes exist. Insulin dependent diabetes mellitus (IDDM), commonly referred to as Type 1 diabetes, is an auto-immune disease that affects the islets of Langerhans, destroying the body's ability to produce insulin. Type 1 diabetes may affect as many as 1 million people in the United States. Non-insulin dependent diabetes mellitus (NIDDM), commonly referred to as Type 2 diabetes, is a metabolic disorder resulting from the body's inability to produce enough insulin or properly use the insulin produced. Roughly 90 percent of all diabetic individuals in the United States suffer from Type 2 diabetes, which is usually associated with obesity and a sedentary lifestyle.
In general, the goal of diabetes treatment is to control glucose level in the blood and maintain it in a range that mimics that of a non-diabetic individual, namely reproduces natural physiological glucose homeostasis. To date, this goal has not been fully effectively achieved.
Diabetes is typically treated by monitoring the glucose level in the body via blood and/or urine sampling and attempting to control the level of glucose in the body using a combination of diet and parenteral injections of insulin. Parenteral injections, such as subcutaneous and intramuscular injections, deliver insulin to the peripheral system. Studies, such as the Diabetes Control and Complications Trial (DCCT), have shown that tight control of blood glucose level to within normal ranges may reduce or eliminate the microvascular complications associated with diabetes. As observed in the DCCT, tight control of blood glucose level may be achievable in some individuals by using three or more daily injections of insulin or by treatment with an insulin pump (continuous subcutaneous insulin infusion). If closely followed, such regimens offer the potential for some control of the disease. However, an increased risk of hypoglycemia was observed in the DCCT when tight control of blood glucose level by peripheral administration was attempted. Additionally, peripheral administration of insulin may result in peripheral hyperinsulinemia, which may increase the risk of various medical complications. Furthermore, many patients may routinely fail to comply with these regimens due to the lack of convenience and/or embarrassment associated with subcutaneous administration of insulin.
In an attempt to overcome the inconvenience and discomfort of subcutaneous administration of insulin, various non-invasive alternatives to injectable insulin have been proposed. For example, U.S. Pat. Nos. 5,320,094 to Laube et al., 5,364,838 to Rubsamen, and 5,997,848 to Patton et al. propose intrapulmonary administration of insulin using inhaler devices. The usefulness of these methods may be limited by the requirement to master the operation of the delivery device, the potential for lung irritation with long-term use, and impaired delivery to those patients with lung disorders. Administration of insulin to the buccal mucosa has also been proposed. While these methods of administration may have been referred to as “oral administration”, they are effectively non-injectable forms of peripheral administration with its attendant problems and difficulties.
Delivery of insulin through nasal mucosa by a spray device has also been proposed. These methods resulted in unacceptable levels of intra-patient, dose-to-dose variability of insulin absorption and also resulted in nasal mucosal irritation. As with the intrapulmonary and buccal mucosa methods described above, delivery of insulin through nasal mucosa is a non-injectable form of peripheral administration.
While these non-injectable forms of peripheral administration may avoid the inconvenience of injectable forms, they still suffer from the same risks of peripheral hyperinsulinemia associated with the peripheral injection of insulin. Furthermore, and perhaps most importantly, they do not effectively deliver insulin to the liver. As described above and in more detail in Goodman & Gilman's, The Pharmacological Basis of Therapeutics 1487-1507 (9th ed. 1996), insulin acts in conjunction with the liver to control glucose metabolism in the body. To achieve more effective treatment of diabetes mellitus, methods should be provided that mimic the natural delivery of insulin to the liver.
Various methods have been proposed that may attempt to mimic the natural delivery of insulin to the liver. For example, U.S. Pat. No. 4,579,730 to Kidron et al. proposes an enterically-coated pharmaceutical composition for the oral administration of insulin. While this patent asserts that the proposed pharmaceutical formulations have the same effect as naturally secreted insulin on the blood glucose levels, the insulin is not rapidly absorbed from the intestinal lumen into the blood stream. For example, the patent reports at column 4, lines 15-16 that only 5-10% of the insulin is absorbed during 60 minutes. Additionally, this formulation appears to have a limited effect on glucose blood levels within the first hour following administration. (See column 4, Table 1).
As another example, U.S. Pat. No. 4,963,526 to Ecanow proposes an oral dosage form of insulin based upon a two-phase liquid aqueous coacervate system that incorporates the insulin in a coacervate phase of the system. The insulin administered using this formulation does not appear to have a rapid effect on glucose blood levels. For example, at column 9, line 52 through column 10, line 12, the patent reports measuring blood glucose levels three hours after administration and observing blood glucose levels of 66.3% and 47.1% of initial blood levels depending on the dosage given.
As still another example, U.S. Pat. No. 4,863,896 to Geho et al. proposes methods of treating diabetes that utilize a combination of peripherally administered insulin and hepatocyte directed vesicles with encapsulated insulin (HDVI). The HDVI will be taken up only by the liver while the separately administered free insulin will supply the needs of the peripheral system. The patent states that the HDVI may be administered orally; however, no dosage ranges are provided. The co-administration of HDVI and peripheral insulin is required because, unlike naturally produced insulin, none of the HDVI will pass through the liver to the peripheral system. (See column 2, lines 3-14).
As yet another example, U.S. Pat. No. 5,704,910 to Humes proposes an implantable device for delivering a pre-selected molecule, for example, a hormone such as insulin, into a mammals systemic circulation. The patent contemplates anchoring an insulin producing device within the portal vein upstream of (i.e., before) the liver. Reliance on such a device to control the life-threatening disease of diabetes mellitus may be impractical. Furthermore, it is unclear what dosages of insulin would be administered by such a device and precisely how the required dosage would be regulated.
In view of the foregoing, there is a need in the art for methods of treating diabetes mellitus that better mimic the natural delivery of insulin to the liver resulting in improved glucose homeostasis in product administration forms that are convenient and easy to use by patients.